Synthesis of 3-substituted 3-(trimethylsiloxy)pyrrolidines from β-aminoketones and lithium trimethylsilyldiazomethane

Article abstract of DOI:10.3987/COM-09-S(S)70

Lithium trimethylsilyldiazomethane reacted with N-benzyl-β-aminoketones at -78 °C in THF to give 3-substituted 1-benzyl-3-(trimethylsiloxy)pyrrolidines in moderate to good yields.

Full text of DOI:10.3987/COM-09-S(S)70

HETEROCYCLES, Vol. 80, No. 1, 2010
679
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 679 - 687. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd July, 2009, Accepted, 25th August, 2009, Published online, 25th August, 2009
DOI: 10.3987/COM-09-S(S)70
SYNTHESIS OF 3-SUBSTITUTED
3-(TRIMETHYLSILOXY)PYRROLIDINES FROM ꢀ-AMINOKETONES
AND LITHIUM TRIMETHYLSILYLDIAZOMETHANE
Yoshiyuki Hari,a Takuya Yokoyama,b and Toyohiko Aoyamab*
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan
b
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1
Tanabedori, Mizuho, Nagoya 467-8603, Japan
E-mail: aoyama@phar.nagoya-cu.ac.jp
Dedicated to Professor Dr. Akira Suzuki on the occasion of his 80th birthday
Abstract
–
Lithium
trimethylsilyldiazomethane
reacted
with
N-benzyl-ꢀ-aminoketones at -78 °C in THF to give 3-substituted
1-benzyl-3-(trimethylsiloxy)pyrrolidines in moderate to good yields.
INTRODUCTION
We have previously reported that lithium trimethylsilyldiazomethane [TMSC(Li)N2] readily reacts with
aliphatic ꢀ-aminoketones to give the corresponding 2-pyrrolines (intramolecular N-H insertion products)
R
TMS
LiO
O
TMSC(Li)N2
C
R = aliphatic
N2
-TMSOLi
-N2
R
NHBn
R
NHBn
N
THF
–78 °C
R
NHBn
1
Bn
4
-N2
R = aromatic
NHBn
OTMS
R
R
N
3
Bn
2
Scheme 1

680
HETEROCYCLES, Vol. 80, No. 1, 2010
in moderate to good yields via alkylidenecarbene intermediates (Scheme 1).1 Furthermore, we have
demonstrated that the reaction of TMSC(Li)N2 with aryl ketones efficiently produces the corresponding
aryl acetylenes (1,2-aryl rearrangement products) also via alkylidenecarbene intermediates.2 Due to our
continued interest in the use of TMSCHN2 in organic synthesis,3 the reaction of TMSC(Li)N2 with
N-benzyl--aminoketones 1 was reexamined in detail. Interestingly, we found that when the reaction was
carried out at low temperature, -78 °C, intramolecular N-alkylation via initially formed diazoalkoxides
preferentially occurred and the 3-substituted 1-benzyl-3-(trimethylsiloxy)pyrrolidines 2 were obtained as
major products (Scheme 1). In this paper, we describe the details of our results.
RESULTS AND DISCUSSION
All N-benzyl--aminoketones 1 used in this study were synthesized from the corresponding
N-methoxy-N-methylamides, vinylmagnesium bromide and benzylamine according to the procedure
reported by Gomtsyan and co-workers (Figure 1).4 Initially, the N-benzyl--aminoketone 1a was
employed as a model substrate to optimize reaction conditions. The results are summarized in Table 1. In
analogy with the reaction with aryl ketones,2 the reaction of TMSC(Li)N2 with 1a at -78 °C for 2 h
followed by reflux for 2 h smoothly proceeded to give the alkyne 3a (50% yield) as a major product, but
an unexpected product, the pyrrolidine 2a, was also obtained in 29% yield (entry 1). Interestingly,
lowering the reaction temperature remarkably affected the reaction mode and 2a was obtained as a major
product (entries 2, 3 and 6-8). The change of the reaction mode at low temperature is most likely due to
suppression of the elimination of lithium trimethylsiloxide (TMSOLi) and N2 gas, which generates an
alkylidenecarbene intermediate, and consequently, intramolecular alkylation of the initially formed
diazoalkoxide preferentially occurs with evolution of N2 to give 2a as shown in Scheme 1. THF was the
reaction solvent of choice to efficiently produce 2a (entries 3 and 4). Replacement of TMSC(Li)N2 by the
magnesium bromide salt [TMSC(MgBr)N2]5 was less effective (entries 3 and 5). The reaction at -78 °C in
THF for 12 h was found to give the best result (entry 7). The structure of 2a was confirmed by alternative
O
O
NHBn
NHBn
R = H (1a)
MeO (1b)
1c
R
Cl (
)
1d
O
O
O
Me
Me
NHBn
NHBn
Ph
NHBn
S
Me
1e
1f
1g
Figure 1. N-Benzyl--aminoketones 1 used in this study

HETEROCYCLES, Vol. 80, No. 1, 2010
681
Table 1. Reaction of TMSC(M)N2 (M = Li or MgBr) with 1aa
OTMS
Ph
O
TMSC(M)N2
NHBn
a
+
Ph
NHBn
N
Ph
solvent, conditions
Bn
2a
1a
3a
Entry
M
Solvent
Conditions
Yield (%)b of 2a
Yield (%)b of 3a
1
2
3
4
5
6
7
8
Li
Li
Li
Li
MgBr
Li
Li
THF
THF
THF
Et2O
THF
THF
THF
THF
-78 °C, 2 h to reflux, 2 h
-78 °C, 2 h to rt, 2 h
-78 °C, 2 h to 0 °C, 2 h
-78 °C, 2 h to 0 °C, 2 h
-78 °C, 2 h to 0 °C, 2 h
-78 °C, 6 h
29
45
49
3
50
33
26
30
21
28
22
22
9
52
56
56
-78 °C, 12 h
-78 °C, 24 h
Li
a, TMSC(Li)N2 was prepared from TMSCHN2 and n-BuLi. TMSC(MgBr)N2 was prepared from TMSCHN2, n-BuLi and MgBr2. b, Isolated yield.
OH
O
Ph
PhMgBr
TMSCl
2a
THF
0 °C, 1.5 h to rt, 18 h
(53 %)
2,6-lutidine, CH2Cl2
0 °C, 7 h
N
N
Bn
Bn
5a
(65%)
Scheme 2
Table 2. The generality of substrates 1
OTMS
R
R
O
TMSC(Li)N2
NHBn
+
+
R
NHBn
THF
–78 °C, 12 h
N
N
R
1
3
Bn
Bn
2
4
Entry
R
Yield (%)b of 2
Yield (%)b of 3
22
43
7
Yield (%)b of 4
1a
2
3
4
5
6
7
Ph (1a)
p-MeOPh (1b)
p-ClPh (1c)
Naphth-2-yl (1d)
Thiophen-2-yl (1e)
tert-Butyl (1f)
PhCH2CH2 (1g)
56
42
31
47
36
60
72
-
-
-
-
c
c
c
c
33
19
c
-
c
-
-
23
c
d
-
a, Shown in entry 7 of Table 1. b, Isolated yield. c, Not obtained. d, An unseparable mixture of the corresponding 2-pyrroline 4g and an unknown product was
obtained.
synthesis from N-benzyl-3-pyrrolidinone, namely the reaction of N-benzyl-3-pyrrolidinone with
phenylmagnesium bromide followed by trimethylsilylation by TMSCl (Scheme 2).
Next, the generality of the substrate was investigated (Table 2). When the substitutent on the benzene ring
was an electron-donating group like a methoxy group (1b), the ratio of the alkyne 3b to the pyrrolidine 2b
increased compared to that of 1a. Conversely, an electron-withdrawing group such as a chloro group (1c)

682
HETEROCYCLES, Vol. 80, No. 1, 2010
preferentially furnished the desired pyrrolidine 2c though the yields of 2c and 3c were somewhat low due
to the inherent lability of 1c.6 In the case of the naphthyl derivative 1d, the reaction proceeded smoothly
to give 2d in 47% yield with 33% yield of 3d (entry 4). This reaction was also applicable to the substrate
1e bearing heteroaromatics like thiophene for R and the desired 2e was obtained in moderate yield (entry
5). The aliphatic -aminoketone 1f also underwent the reaction to give the desired 2f in good yield (60%)
though the pyrroline 4f was formed as by-product (entry 6). Similarly, phenethyl derivative 1g gave 2g in
72% yield (entry 7).
CONCLUSION
We found that reaction of TMSC(Li)N2 with -aminoketones at -78 °C mainly proceeded in an
intramolecular N-alkylation mode, and 3-substituted 3-(trimethylsiloxy)pyrrolidines were obtained in
moderate to good yields. The present method is a new application of TMSC(Li)N2 as a reagent in organic
synthesis.
EXPERIMENTAL
All melting points were measured on a Yanagimoto micro melting points apparatus and are uncorrected.
1
13
IR spectra were recorded on a SHIMADZU FTIR-8400S spectrophotometer. H and C NMR spectra
13
were recorded on a JEOL JNM-EX-270 spectrometer (1H, 270 MHz; C, 67.8 MHz). MS spectra were
recorded on a JEOL JMS-SX-102A spectrometer. Silica gel used for column chromatography is Fuji
Sylisia BW-820MH.
General procedure for the synthesis of N-benzyl--aminoketone (1).4 Under an argon atmosphere,
vinylmagnesium bromide (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a solution of
N-methoxy-N-methylamide derivative (10 mmol) in THF (100 mL) at 0 °C and the mixture was stirred
for 10 min, then stirred at room temperature for 1 h. A solution of BnNH2 (1.0 M in water, 15 mL, 15
mmol) was added and the mixture was stirred at room temperature for 20 min-2 h. The mixture was
extracted with EtOAc. The organic extracts were washed with H2O and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the
following product.
3-(Benzylamino)-1-phenylpropan-1-one (1a).4 Prepared from N-methoxy-N-methylbenzamide. EtOAc
was used as eluent for column chromatography. 70% yield.
3-(Benzylamino)-1-(4-methoxyphenyl)propan-1-one (1b). Prepared from 4-methoxy-N-methoxy-N-
methylbenzamide.7 EtOAc was used as eluent for column chromatography. 88% yield. Yellow oil. IR
1
(neat): 3319, 1672, 1258 cm-1. H-NMR (CDCl3) : 1.72 (brs, 1H), 3.03 (t, J = 5.9 Hz, 2H), 3.16 (t, J =
5.9 Hz, 2H), 3.83 (s, 2H), 3.86 (s, 3H), 6.91-6.94 (d, J = 8.9 Hz, 2H), 7.31-7.33 (m, 5H), 7.91-7.95 (d, J =

HETEROCYCLES, Vol. 80, No. 1, 2010
683
13
8.9 Hz, 2H). C-NMR (CDCl3) : 38.43, 44.37, 54.15, 55.48, 113.66, 126.83, 126.96, 128.02, 128.31,
128.44, 130.18, 140.02, 197.94. EI-MS m/z: 269 (M+), 135 (bp).
3-(Benzylamino)-1-(4-chlorophenyl)propan-1-one (1c). Prepared from 4-chloro-N-methoxy-N-
methylbenzamide.8 EtOAc was used as eluent for column chromatography. 41% yield. Yellow oil. IR
(neat): 1682 cm-1. 1H-NMR (CDCl3) : 1.83 (brs, 1H), 3.03 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H),
3.83 (s, 2H), 7.23-7.33 (m, 5H), 7.42 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H). 13C-NMR (CDCl3) :
38.92, 44.07, 54.15, 126.85, 127.97, 128.31, 128.81, 129.30, 135.09, 139.46, 140.01, 198.14. EI-MS m/z:
275 (M+), 273 (M+), 139 (bp). HR-MS calcd for C16H1635ClNO: 273.0920, found: 273.0910. HR-MS
calcd for C16H1637ClNO: 275.0891, found: 275.0867.
3-(Benzylamino)-1-(naphthalen-2-yl)propan-1-one (1d). Prepared from N-methoxy-N-methyl-2-
naphthamide [Yellow oil. IR (neat): 1643 cm-1. 1H-NMR (CDCl3) : 3.42 (s, 3H), 3.57 (s, 3H), 7.52-7.58
(m, 2H), 7.74-7.77 (m, 1H), 7.85-7.92 (m, 3H), 8.22 (s, 1H). 13C-NMR (CDCl3) : 33.87, 61.06, 124.90,
126.31, 127.21, 127.45, 127.53, 128.51, 128.66, 131.25, 132.32, 134.05, 169.66. EI-MS m/z: 215 (M+),
155 (bp). HR-MS calcd for C13H13NO2: 215.0946, found: 215.0945.].9 Hexane-EtOAc (2:1 to 0:1) was
used as eluent for column chromatography. 55% yield. Yellow solid, mp 66-69 °C. IR (neat): 3303, 1672
cm-1. 1H-NMR (CDCl3) : 1.91 (brs, 1H), 3.13 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 6.2 Hz, 2H), 3.90 (s, 2H),
7.28-7.38 (m, 5H), 7.55-7.66 (m, 2H), 7.89-8.07 (m, 4H), 8.49 (s, 1H). 13C-NMR (CDCl3) : 38.92, 44.28,
54.17, 123.57, 126.65, 126.81, 127.63, 127.99, 128.29, 128.33, 128.36, 129.44, 129.64, 132.31, 134.03,
135.44, 140.04, 199.35. EI-MS m/z: 289 (M+), 155 (bp). HR-MS calcd for C20H19NO: 289.1467, found:
289.1462.
3-(Benzylamino)-1-(thiophen-2-yl)propan-1-one (1e). Prepared from N-methoxy-N-methylthiophene-2-
carboxamide.10 Hexane-EtOAc (2:1) was used as eluent for column chromatography. 55% yield. Yellow
oil. IR (neat): 3315, 1658 cm-1. 1H-NMR (CDCl3) : 1.76 (brs, 1H), 3.03 (t, J = 5.8 Hz, 2H), 3.15 (t, J =
5.8 Hz, 2H), 3.83 (s, 2H), 7.12 (m, 1H), 7.23-7.33 (m, 5H), 7.62-7.64 (m, 1H), 7.70-7.71 (m, 1H).
13C-NMR (CDCl3) : 39.54, 44.30, 54.07, 126.84, 127.99, 128.02, 128.31, 131.90, 133.61, 139.96,
144.07, 192.29. EI-MS m/z: 245 (M+), 111 (bp). HR-MS calcd for C14H15NOS: 245.0874, found:
245.0860.
1-(Benzylamino)-4,4-dimethylpentan-3-one (1f). Prepared from N-methoxy-N-methyl-2,2,2-
trimethylacetamide.11 Hexane-EtOAc (1:1) was used as eluent for column chromatography. 69% yield.
1
Yellow oil. IR (neat): 2966, 1699 cm-1. H-NMR (CDCl3) : 1.14 (s, 9H), 1.77 (brs, 1H), 2.73 (t, J = 5.8
Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 3.78 (s, 2H), 7.20-7.32 (m, 5H). 13C-NMR (CDCl3) :26.37, 26.49,
36.84, 44.16, 54.21, 126.79, 127.97, 128.28, 140.10, 215.53. EI-MS m/z: 219 (M+), 91 (bp).
1-(Benzylamino)-5-phenylpentan-3-one
(1g).
Prepared
from
N-methoxy-N-methyl-3-

684
HETEROCYCLES, Vol. 80, No. 1, 2010
phenylpropanamide.12 Hexane-EtOAc (1:1) was used as eluent for column chromatography. 74% yield.
Yellow oil. IR (neat): 3026, 1713 cm-1. 1H-NMR (CDCl3) : 1.71 (s, 1H), 2.60 (t, J = 6.2 Hz, 2H), 2.73 (t,
J = 7.2 Hz, 2H), 2.84 (t, J = 6.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 3.75 (s, 2H), 7.14-7.33 (m, 10H).
13C-NMR (CDCl3) : 29.68, 43.11, 43.81, 44.49, 54.06, 125.99, 126.82, 127.95, 128.15, 128.27, 128.36,
140.00, 140.81. EI-MS m/z: 267 (M+), 91 (bp). HR-MS calcd for C18H21NO: 267.1623, found: 267.1624.
General procedure of reaction between TMSC(Li)N2 and N-benzyl--aminoketones (1). Under an
argon atmosphere, a solution of 1 (1.0 mmol) in THF (3 mL) was added dropwise to a solution of
TMSC(Li)N2, prepared from TMSCHN2 (2.17 M in hexane, 0.55 mL, 1.2 mmol) and n-BuLi (1.59 M in
hexane, 0.75 mL, 1.2 mmol) in THF (10 mL), at -78 °C, and the mixture was stirred at -78 °C for 12 h.
After being quenched with H2O, the mixture was extracted with EtOAc. The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give the following products.
1-Benzyl-3-phenyl-3-(trimethylsilyloxy)pyrrolidine (2a) and N-benzyl-4-phenylbut-3-yn-1-amine
(3a). Hexane-EtOAc (10:1 to 2:1) was used as eluent for column chromatography. 2a: 56% yield. Yellow
oil. IR (neat): 1250, 1109 cm-1. 1H-NMR (CDCl3) : 0.15 (s, 9H), 2.33-2.41 (m, 2H), 2.76-2.84 (m, 1H),
13
2.95-3.09 (m, 3H), 3.71, 3.85 (ABq, J = 12.9 Hz, 2H), 7.26-7.57 (m, 10H). C-NMR (CDCl3) : 2.14,
42.57, 53.70, 60.66, 69.23, 83.62, 125.34, 126.49, 126.80, 127.77, 128.09, 128.68, 139.01, 147.45. EI-MS
m/z: 325 (M+), 133 (bp). HR-MS calcd for C20H27NOSi: 325.1859, found: 325.1862. 3a: 22% yield.
Yellow oil. IR (neat): 3028, 2229 cm-1. 1H-NMR (CDCl3) : 2.00 (br, 1H), 2.65 (t, J = 6.6 Hz, 2H), 2.90
13
(t, J = 6.6 Hz, 2H), 3.87 (s, 2H), 7.27-7.43 (m, 10H). C-NMR (CDCl3) : 20.63, 47.62, 53.39, 82.04,
87.86, 126.83, 127.57, 127.95, 128.05, 128.27, 128.39, 128.44, 131.45. EI-MS m/z: 235 (M+), 91 (bp).
HR-MS calcd for C17H17N: 235.1359, found: 235.1361.
1-Benzyl-3-(4-methoxyphenyl)-3-(trimethylsilyloxy)pyrrolidine
(2b)
and
N-benzyl-4-(4-
methoxyphenyl)but-3-yn-1-amine (3b). Hexane-EtOAc (5:1 to 2:1) was used as eluent for column
chromatography. 2b: 42% yield. Yellow oil. IR (neat): 1248, 1103 cm-1. 1H-NMR (CDCl3) : 0.03 (s, 9H),
2.19-2.26 (m, 2H), 2.65-2.73 (m, 1H), 2.83-2.96 (m, 3H), 3.67 (ABq, J = 12.4 Hz, 2H), 3.76 (s, 3H),
13
6.79-6.83 (m, 2H), 7.18-7.35 (m, 7H). C-NMR (CDCl3) : 2.11, 42.12, 53.26, 55.25, 60.77, 68.94,
83.29, 113.11, 126.61, 126.81, 128.09, 128.69, 130.92, 138.95, 158.17. EI-MS m/z: 355 (M+), 263 (bp).
HR-MS calcd for C21H29O2NSi: 355.1968, found: 355.1959. 3b: 43% yield. Yellow oil. IR (neat): 2928,
1
2046, 1246 cm-1. H-NMR (CDCl3) : 1.26 (br, 1H), 2.58 (t, J = 7.3 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H),
13
3.75 (s, 2H), 3.79 (s, 3H), 6.78-6.98 (m, 3H), 7.23-7.98 (m, 6H). C-NMR (CDCl3) : 20.68, 47.77,
53.46, 55.30, 81.54, 86.26, 113.78, 115.74, 126.86, 128.02, 128.33, 132.84, 140.13, 159.04. EI-MS m/z:
265 (M+), 91 (bp). HR-MS calcd for C18H19NO: 265.1467, found: 265.1470.

HETEROCYCLES, Vol. 80, No. 1, 2010
685
1-Benzyl-3-(4-chlorophenyl)-3-(trimethylsilyloxy)pyrrolidine
(2c)
and
N-benzyl-4-(4-
chlorophenyl)but-3-yn-1-amine (3c). Hexane-EtOAc (20:1 to 2:1) was used as eluent for column
chromatography. 2c: 31% yield. Yellow oil. IR (neat): 1250, 1094 cm-1. 1H-NMR (CDCl3): 0.07 (s, 9H),
2.24 (t, J = 7.1 Hz, 2H), 2.72-2.75 (m, 1H), 2.84-2.90 (m, 3H), 3.61, 3.76 (ABq, J = 12.9 Hz, 2H),
7.24-7.42 (m, 9H). 13C-NMR (CDCl3) : 2.16, 42.68, 53.24, 60.50, 69.13, 83.14, 126.73, 126.89, 127.85,
128.14, 128.66, 132.15, 138.77, 146.43. EI-MS m/z: 361 (M+), 359 (M+), 133 (bp). HR-MS calcd for
C20H2635ClNOSi: 359.1472, found: 359.1466. HR-MS calcd for C20H2637ClNOSi: 361.1443, found:
361.1434. 3c: 7% yield. Yellow oil. IR (neat): 2924, 2228 cm-1. 1H-NMR (CDCl3): 2.35 (brs, 1H), 2.63
(t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 3.85 (s, 2H), 7.23-7.34 (m, 9H). 13C-NMR (CDCl3) : 20.61,
47.43, 53.35, 80.77, 88.91, 122.02, 126.99, 128.04, 128.37, 128.43, 132.73, 133.61, 139.78. EI-MS m/z:
271 (M+), 269 (M+), 91 (bp). HR-MS calcd for C17H1635ClN: 269.0971, found: 269.0959.
1-Benzyl-3-(naphthalen-2-yl)-3-(trimethylsilyloxy)pyrrolidine (2d) and N-benzyl-4-(naphthalen-2-
yl)but-3-yn-1-amine (3d). Hexane-EtOAc (15:1 to 1:1) was used as eluent for column chromatography.
1
2d: 47% yield. Yellow oil. IR (neat): 1250, 1040 cm-1. H-NMR (CDCl3) : 0.07 (s, 9H), 2.26-2.47 (m,
2H), 2.74-2.82 (m, 1H), 2.89-3.08 (m, 3H), 3.65, 3.81 (ABq, J = 13.0 Hz, 2H), 7.21-7.48 (m, 7H),
13
7.59-7.63 (m, 1H), 7.77-7.88 (m, 4H). C-NMR (CDCl3) : 2.19, 42.51, 53.42, 60.63, 69.01, 83.67,
123.24, 124.52, 125.49, 125.80, 126.83, 127.32, 127.56, 128.05, 128.11, 128.67, 132.18, 132.78, 138.96,
144.80. EI-MS m/z: 375 (M+), 91 (bp). HR-MS calcd for C24H29ONSi: 375.2019, found: 375.2018. 3d:
33% yield. Yellow oil. IR (neat): 2945, 2230 cm-1. 1H-NMR (CDCl3) : 2.13 (br, 1H), 2.68 (t, J = 6.6 Hz,
13
2H), 2.90 (t, J = 6.6 Hz, 2H), 3.85 (s, 2H), 7.21-7.46 (m, 8H), 7.72-7.91 (m, 4H). C-NMR (CDCl3):
20.64, 47.50, 53.31, 82.04, 88.21, 120.71, 126.18, 126.81, 127.39, 127.49, 127.66, 127.94, 128.25, 128.42,
131.01, 132.29, 132.74, 139.88. EI-MS m/z: 285 (M+), 91 (bp). HR-MS calcd for C21H19N: 285.1518,
found: 285.1521.
1-Benzyl-3-(thiophen-2-yl)-3-(trimethylsilyloxy)pyrrolidine (2e) and N-benzyl-4-(thiophen-2-yl)but-
3-yn-1-amine (3e). Hexane-EtOAc (10:1 to 2:1) was used as eluent for column chromatography. 2e: 36%
1
yield. Yellow oil. IR (neat): 1250, 1030 cm-1. H-NMR (CDCl3) : 0.07 (s, 9H), 2.30-2.37 (m, 2H),
2.68-2.73 (m, 1H), 2.71-3.03 (m, 3H), 3.63, 3.75 (ABq, J = 13.0 Hz, 2H), 6.91-6.93 (m, 2H), 7.14-7.33
13
(m, 6H). C-NMR (CDCl3) : 1.89, 43.02, 52.75, 60.43, 69.32, 81.68, 122.01, 123.63, 126.32, 126.83,
128.09, 128.64, 138.78, 153.03. EI-MS m/z: 331 (M+), 133 (bp). HR-MS calcd for C18H25NOSSi:
1
331.1426, found: 331.1434. 3e: 19% yield. Yellow oil. IR (neat): 3026, 2226 cm-1. H-NMR (CDCl3) :
1.25 (s, 1H), 2.65 (t, J = 6.6 Hz, 2H), 2.86 (t, J = 6.6 Hz, 2H), 3.84 (s, 2H), 6.91-6.94 (m, 1H), 7.12-7.34
(m, 7H). 13C-NMR (CDCl3) : 20.81, 47.27, 53.29, 74.89, 91.90, 123.49, 126.07, 126.65, 126.88, 127.99,
128.30, 131.14, 139.75. EI-MS m/z: 241 (M+), 91 (bp). HR-MS calcd for C15H15NS: 241.0925, found:

686
HETEROCYCLES, Vol. 80, No. 1, 2010
249.0916.
1-Benzyl-3-tert-butyl-3-(trimethylsilyloxy)pyrrolidine (2f) and 1-benzyl-4-tert-butyl-2,3-dihydro-
1H-pyrrole (4f). Hexane-EtOAc (50:1 to 5:1) was used as eluent for column chromatography. 2f: 60%
1
yield. Yellow oil. IR (neat): 1248, 1036 cm-1. H-NMR (CDCl3): 0.11 (s, 9H), 0.89 (s, 9H), 1.65 (m,
1H), 2.08 (m, 2H), 2.43, 2.63 (ABq, J = 10.0 Hz, 2H), 2.82 (m, 1H), 3.34, 3.74 (ABq, J = 12.7 Hz, 2H),
13
7.26-7.32 (m, 5H). C-NMR (CDCl3): 2.26, 25.69, 35.25, 37.57, 53.57, 60.70, 62.67, 88.26, 126.72,
128.00, 128.80, 139.16. EI-MS m/z: 305 (M+), 91 (bp). HR-MS calcd for C18H31ONSi: 305.2175, found:
1
305.2170. 4f: 23% yield. Yellow oil. IR (neat): 1678 cm-1. H-NMR (270 MHz, CDCl3): 1.04 (s, 9H),
2.39 (td, J = 8.7, 1.5 Hz, 2H), 2.90 (t, J = 8.7 Hz, 2H), 3.77 (s, 2H), 5.61 (d, J = 1.5 Hz, 1H), 7.26-7.34 (m,
13
5H). C-NMR (CDCl3) : 29.47, 29.77, 31.20, 54.43, 59.53, 126.90, 128.18, 128.44, 128.60, 132.27,
138.72. EI-MS m/z: 215 (M+), 91 (bp). HR-MS calcd for C15H21N: 215.1674, found: 215.1684.
1-Benzyl-3-phenethyl-3-(trimethylsilyloxy)pyrrolidine (2g). Hexane-EtOAc (10:1) was used as eluent
for column chromatography. 72% yield. Yellow oil. IR (neat): 1250, 1040 cm-1. 1H-NMR (CDCl3): 0.22
(s, 9H), 1.92-2.01 (m, 4H), 2.48-2.59 (m, 2H), 2.68-2.85 (m, 4H), 3.57, 3.74 (ABq, J = 12.9 Hz, 2H),
13
7.23-7.38 (m, 10H). C-NMR (CDCl3): 2.41, 30.94, 39.69, 44.61, 52.98, 60.52, 66.98, 82.60, 125.49,
126.76, 128.04, 128.20, 128.24, 128.65, 138.95, 142.73. EI-MS m/z: 353 (M+), 91 (bp). HR-MS calcd for
C22H31NOSi: 353.2175, found: 353.2168.
Alternative synthesis of 2a from 1-benzylpyrrolidin-3-one. Under an argon atmosphere,
phenylmagnesium bromide (1.09 M THF solution, 1.0 mL, 1.1 mmol) was added dropwise to a solution
of 1-benzylpyrrolidin-3-one (0.16 mL, 1.0 mmol) in THF (10 mL) at 0 °C and the mixture was stirred for
1.5 h, then stirred for 18 h at room temperature. The mixture was extracted with EtOAc. The organic
extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography
on
silica
gel
using
hexane-EtOAc
(1:1)
as
eluent
to
give
1-benzyl-3-phenylpyrrolidin-3-ol (134 mg, 53 %) [Yellow oil. IR (neat): 3414 cm-1. 1H-NMR (CDCl3) :
2.18-2.26 (m, 1H), 2.32-2.43 (m, 1H), 2.51-2.66 (m, 2H), 2.97-3.00 (m, 1H), 3.12-3.20 (m, 1H), 3.74 (s,
13
2H), 7.21-7.36 (m, 8H), 7.48-7.51 (m, 2H). C-NMR (CDCl3) : 41.86, 52.65, 59.89, 68.39, 80.65,
125.09, 126.90, 127.03, 128.06, 128.23, 128.66, 138.44, 143.92. EI-MS m/z: 253 (M+), 91 (bp). HR-MS
calcd for C17H19NO: 253.1467, found: 253.1464.]. Under an argon atmosphere, 2,6-lutidine (0.23 mL, 2.0
mmol) and TMSCl (0.10 mL, 0.75 mmol) were added to a solution of 1-benzyl-3-phenylpyrrolidin-3-ol
(127 mg, 0.5 mmol) in CH2Cl2 (3 mL) at 0 °C and the mixture was stirred for 7 h. After addition of brine,
the mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, and concentrated in
vacuo. The residue was purified by column chromatography on silica gel using hexane-EtOAc (10:1) to
give 2a (106 mg, 65%).

HETEROCYCLES, Vol. 80, No. 1, 2010
687
ACKNOWLEDGEMENTS
This work was financially supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the
Japan Society for the Promotion of Science, and Special Coordination Funds for Promoting Science and
Technology of the Ministry of Education, Culture, Sports, Science and Technology, Japan.
REFERENCES AND NOTES
1. T. Yagi, T. Aoyama, and T. Shioiri, Synlett, 1997, 1063.
2. K. Miwa, T. Aoyama, and T. Shioiri, Synlett, 1994, 107.
3. CAUTION: Two deaths were recently reported from use of TMSCHN2 without proper ventilation. D.
F. Taber, Org. Chem. Highlights, 2009, Jun 8, http://www.organic-chemistry.org.
4. A. Gomtsyan, R. J. Koenig, and C.-H. Lee, J. Org. Chem., 2001, 66, 3613.
5. Reactions using TMSC(MgBr)N2. Y. Hari, S. Tsuchida, and T. Aoyama, Tetrahedron Lett., 2006, 47,
1977; Y. Hari, S. Tsuchida, R. Sone, and T. Aoyama, Synthesis, 2007, 3371; Y. Hari, K. Date, R.
Kondo, and T. Aoyama, Tetrahedron Lett., 2008, 49, 4965; Y. Hari, R. Sone, and T. Aoyama, Org.
Biomol. Chem., 2009, 7, 2804.
6. The inherent lability of 1c might be due to bimolecular condensation which produces an enamine.
7. J. R. Martinelli, D. M. M. Freckmann, and S. L. Buchwald, Org. Lett., 2006, 8, 4843.
8. A. Leggio, A. Liguori, A. Napoli, C. Siciliano, and G. Sindona, J. Org. Chem., 2001, 66, 2246.
9. J. M. Kraus, C. L. M. J. Verlinde, M. Karimi, G. I. Lepesheva, M. H. Gelb, and F. S. Buckner, J.
Med. Chem., 2009, 52, 1639.
10. J. M. White, A. R. Tunoori, B. J. Turunen, and G. I. Georg, J. Org. Chem., 2004, 69, 2573.
11. J. C. S. Woo, E. Fenster, and G. R. Dake, J. Org. Chem., 2004, 69, 8984.
12. J. A. Murphy, A. G. J. Commeureuc, T. N. Snaddon, T. M. McGuire, T. A. Khan, K. Hisler, M. L.
Dewis, and R. Carling, Org. Lett., 2005, 7, 1427.